PDF file - 111K, Human Proneural tumors are relatively enriched in OPC genes. Expression profiles of 202 gliomas from TCGARN were analyzed, grouped into the four subclasses (2) A: Using gene symbol to map human and mouse homologues, highly significant enrichment of OPC genes in the human 'proneural' specific gene lists was identified (Chi-square p < 5E-31), but not in the other human glioma gene lists. Percent of tumor subclass specific gene lists overlapping with OPC specific genes. **** p<1E-32, + p<.06, Chi-square. All gene lists used pSI<.01 as a cut-off. B: Hierarchical clustering with just OPC genes is sufficient to distinguish most proneural tumors from other tumor subtypes. C: Expression level of average of OPC genes is higher in 'proneural' tumors though they are present at detectable levels in all subtypes. *p<.003, **p<.003, ***p<1E-7, ANOVA with Tukey Post Hocs.
ARTICLE ABSTRACT
Platelet-derived growth factor receptor alpha–positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies. Cancer Res; 72(18); 4856–68. ©2012 AACR.
